Formulations Containing Expectorants or Decongestants

ABSTRACT

The present invention relates to bioavailable fill compositions containing one or more of a decongestant, an expectorant, an antitussive, an analgesic, and/or an antihistamine; capsules filled with the bioavailable fill compositions; and methods of making same.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Provisional Application No.62/476,998 filed on Mar. 27, 2017. The content of the application isincorporated herein by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to bioavailable fill compositions containing oneor more of a decongestant, an expectorant, an antitussive, an analgesic,and/or an antihistamine; capsules filled with the bioavailable fillcompositions; and methods of making same.

BACKGROUND OF THE INVENTION

Combinations of various medications are frequently taken by patientssuffering from colds or other viral or bacterial infections, especiallyrespiratory infections. Combination medicines in a unitary formulationare sought for their convenience. For example, a highly concentratedsolution of the medications allows the entire combination to beencapsulated in a reasonable small sized (0.2-1.8 mL) clear softgelcapsule for easy swallowing. It also enhances the bioavailability of themedications. However, some medications such as acetaminophen, tend torecrystallize in such a solution. There is a need for clear, highlyconcentrated formulations suitable for encapsulation in capsules, suchas softgel capsules, and related preparation methods.

SUMMARY OF INVENTION

This invention relates to a new formulation providing desirablecombinations of active ingredients, particularly a combination of two ormore of decongestant, expectorant, antitussive, analgesic, and/orantihistamine in a unitary formulation. This formulation providesconvenience to a patient and aids compliance in taking the medications.The formulation can be free of any ionizing agent; namely, a compound oragent (such as alkali metal ions, i.e., lithium, sodium, potassium,rubidium, and cesium cations) capable of ionizing an active ingredient(e.g., acetaminophen here) in a solution.

An overall approach to formulating the combination of the activeingredients (AIs) is to prepare a fill composition and encapsulate itwith a capsule, such as a soft gelatin capsule (softgel), specificallysolubilizing the AIs in a suitable matrix comprising a polymericsolubilizing agent and water in an alkylene glycol and poly(alkyleneglycol) vehicle.

In one aspect, the invention features a clear bioavailable liquidcomposition (e.g., softgel or hard shell fill composition) comprising:(a) two or more active ingredients selected from the group consistingof: acetaminophen, guaifenesin, phenylephrine and/or a pharmaceuticallyacceptable salt thereof, dextromethorphan and/or a pharmaceuticallyacceptable salt thereof, diphenhydramine and/or a pharmaceuticallyacceptable salt thereof, and pseudoephedrine and/or a pharmaceuticallyacceptable salt thereof; (b) a matrix comprising: 20-70 wt % (e.g.,30-70, 40-60, 45-60, 45-57%, or 46-56%) of a pharmaceutically acceptablepoly(alkylene glycol) (e.g., PEG 400 or PEG 600), and 0.5-8 wt % (e.g.,1-7, 1-6, 1.5-5, 1.5-4.5, 1.9-4.1%) of a pharmaceutically acceptablealkylene glycol; and (c) a solubilizing agent comprising: 1-30 wt %(e.g., 1-25, 2-20, 3-20, 4-20, or 5-18%) of a pharmaceuticallyacceptable polymeric solubilizing agent (e.g., Povidone) and 1-10 wt %(e.g., 2-10, 3-10, 5-10, 5.0-9.5, or 6.0-9.5%) by weight water. The wt %values are based on the total weight of the composition, and whereinsaid fill composition is clear.

In one example, the matrix comprises 45-57 wt % of a pharmaceuticallyacceptable poly(alkylene glycol), and 1.5-4.5 wt % of a pharmaceuticallyacceptable alkylene glycol. In another, the matrix comprises 46-56 wt %of a pharmaceutically acceptable poly(alkylene glycol), and 1.9-4.1 wt %of a pharmaceutically acceptable alkylene glycol.

In one example, the solubilizing agent comprises 4-20 wt % of apharmaceutically acceptable polymeric solubilizing agent, and 5-9.5 wt %by weight water. In another, the solubilizing agent comprises 5-18 wt %of a pharmaceutically acceptable polymeric solubilizing agent, and6.0-9.5 wt % by weight water.

In some embodiments, the clear bioavailable liquid composition comprise:

0 to about 30.0 wt % (e.g., 20-28, 21-27, 22-25, or 22.5-26.5%)acetaminophen,

0 to about 25.0 wt % (e.g., 10-25, 14-24, or 14-23.5%) guaifenesin,

0 to about 1.0 wt % (e.g., 0.1-0.9, 0.2-0.7, 0.5-0.7, or 0.3-0.6%)phenylephrine HCl.

0 to about 2.0 wt % (e.g., 0.5-1.5, 1.0-1.30, or 1.10-1.25%)dextromethorphan HBr,

0 to about 3.0 wt % (e.g., 1.0-3.0, 1.5-2.5, or 1.9-2.1%)diphenhydramine HCl, or

0 to about 5.0 wt % (e.g., or 1.0-4.0, 2.0-4.0, or 3.0-3.5%)pseudoephedrine HCl.

In one embodiment, the clear bioavailable liquid composition comprisesthe following as the only active ingredients: about 22.0 to about 25.0wt % (e.g., about 23-24, 23.0-23.5, or 23.26%) guaifenesin and about 0.5to 0.7 wt % (e.g., about 0.55-0.65, 0.57-0.63, or 0.60%) phenylephrineHCl. For example, the clear bioavailable liquid composition can be about860 mg comprising about 200 mg guaifenesin and about 5.13 mgphenylephrine HCl. The composition can further comprise about 404.87 mgpolyethylene glycol 400, about 20 mg propylene glycol, about 150 mgPovidone (k12), and about 80 mg water.

In one embodiment, the clear bioavailable liquid composition comprisesthe following as the only active ingredients: about 22.0 to about 25.0wt % (e.g., about 23-24, 23.0-23.5, or 23.12%) guaifenesin and about 1.0to 2.0 wt % (e.g., about 1.0-1.8, 1.1-1.5, or 1.22%) dextromethorphanHBr (95%). For example, the clear bioavailable liquid composition can beabout 865 mg comprising about 200 mg guaifenesin and about 10.526 mgdextromethorphan HBR (95%). The composition can further comprise about404.474 mg polyethylene glycol 400, about 20 mg propylene glycol, about150 mg Povidone (k12), and about 80 mg water.

In one embodiment, the clear bioavailable liquid composition comprisesthe following as the only active ingredients: about 21.0 to about 24.0wt % guaifenesin (e.g., about 22-23, 22.5-23.0, or 22.6%), about 0.40 toabout 1.0 wt % (e.g., about 0.4-0.6, 0.5-0.6, or 0.59%) phenylephrineHCl, and about 1.0 to 2.0 wt % (e.g., about 1.10-1.50, 1.10-1.20, or1.19%) dextromethorphan HBr (95%). For example, the clear bioavailableliquid composition can be about 885 mg comprising about 200 mgguaifenesin, about 5.25 mg phenylephrine HCl, and about 10.526 mgdextromethorphan HBr (95%). The composition can further comprise about419.224 mg polyethylene glycol 400, about 20 mg propylene glycol, about150 mg Povidone (k12), and about 80 mg water.

In one embodiment, the clear bioavailable liquid composition comprisesthe following as the only active ingredients: 21.0 to about 24.0 wt %(e.g., about 22-23, 22.5-23.0, or 22.97%) acetaminophen, 13.0 to about16.0 wt % (e.g., about 14-15, 14.0-14.5, or 14.13%) guaifenesin, and 0.2to about 0.6 wt % (e.g., about 0.3-0.5, 0.35-0.4, or 0.37%)phenylephrine HCl. For example, the clear bioavailable liquidcomposition can be 1415 mg comprising about 325 mg acetaminophen, about200 mg guaifenesin and about 5.25 mg phenylephrine HCl The compositioncan further comprise about 671.75 mg polyethylene glycol 400, about 28mg propylene glycol, about 100 mg Povidone (k12), and about 85 mg water.

In one embodiment, the clear bioavailable liquid composition comprisesthe following as the only active ingredients: 25.0 to about 28.0 wt %(e.g., about 26-27, 26.0-26.5, or 26.21%) acetaminophen, 0.30 to about0.60 wt % (e.g., about 0.4-0.5, 0.40-0.45, or 0.42%) phenylephrine HCl,and 1.0 to about 3.0 wt % (e.g., about 1.5-2.5, 2.0-2.5, or 2.02%)diphenhydramine HCl. For example, the clear bioavailable liquidcomposition can be about 1240 mg comprising about 325 mg acetaminophen,about 5.25 mg phenylephrine HCl and about 25 mg diphenhydramine HCl. Thecomposition can further comprise about 684.75 mg polyethylene glycol400, about 50 mg propylene glycol, about 65 mg Povidone (k30), and about85 mg water.

In yet another embodiment, the clear bioavailable liquid compositioncomprises the following as the only active ingredients: about 21.0 toabout 25.0 wt % (e.g., about 21-24, 22-24, or 22.5-23.0%) guaifenesinand about 2 to 5 wt % (e.g., about 2-4, 3-4 or 3.20-3.60%)pseudoephedrine HCl. For example, the clear bioavailable liquidcomposition can be about 850-890 mg comprising about 200 mg guaifenesinand about 30 mg pseudoephedrine HCl.

The above described clear bioavailable liquid composition comprises onlytwo or three active ingredients selected from the group. The two orthree active ingredients are the only active ingredients.

In another aspect, the invention provides a pharmaceutical compositionin the form of a capsule (e.g., a soft gelatin capsule or a hard shellcapsule) of a size suitable (e.g., 0.2-1.8 mL, 0.3-1.5, or 0.5-1.0 ml)for easy swallowing and typically containing from about 100 mg to about2000 mg of a solubilized pharmaceutical active composition, comprising:(a) an outer shell (e.g., gelatin shell); and (b) a safe and effectivemount of the clear bioavailable liquid composition described above,which is encapsulated by said outer shell.

Another aspect of the invention is directed to a softgel capsulecomprising a soft gelatin capsule filled with the bioavailable liquidsoftgel fill composition disclosed above. In one embodiment the gelatinof said soft gelatin (softgel) capsule comprises bovine-, avian-,porcine-, marine- or vegetable-based gelatin, or a mixture of two ormore thereof. In one embodiment, the softgel capsule further comprisesan enteric coating. The enteric coating preferably comprises acontrolled release or delayed release polymer. In one embodiment thecontrolled release polymer is an acid-resistant polymer.

Another aspect of the invention is directed to a bioavailable liquidfill composition consisting essentially of or consisting of thecomponents described above.

The details of one or more embodiments of the invention are set forth inthe description below. Other features, objectives, and advantages of theinvention will be apparent from the description and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a chart showing an exemplary process flow for gel masspreparation.

FIG. 2 is a chart showing an exemplary process flow for a fillpreparation.

FIG. 3 is a chart of showing an exemplary process flow for encapsulationand post-process.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides a clear, liquid pharmaceutical formulation thatcontains a combination two or more of a decongestant, an expectorant, anantitussive, an analgesic, and/or an antihistamine. It was unexpectedthat the formulation can be prepared in a small size suitable for easyswallowing as a clear liquid and remain clear without recrystallizationfor an extended period of time (8 days up to 2 years) despite the highlyconcentrated active ingredients (such as two or more of acetaminophen,guaifenesin, phenylephrine, dextromethorphan, diphenhydramine, andpseudoephedrine). The formulation is suitable for preparing various oraldosage forms, e.g., soft gel capsule, suspension, solution, syrup,two-piece hard shell capsule, and nasal/oral spray. See ModernPharmaceutics, Volume 121 (2004), edited by Gilbert S. Banker andChristopher T. Rhodes, and references cited therein. See also U.S. Pat.Nos. 8,518,438, and 8,969,416, and International Patent Application No.PCT/US16/54052. These documents are hereby incorporated by reference intheir entirety.

In particular, it may be used to prepare capsules (e.g., soft gels)containing a high dose of the combination in a stable solution. In thatcase, an overall approach to formulating the combination of the activeingredients (AIs) is to prepare a fill composition and encapsulate itwith a capsule, such as a soft gelatin capsule, specificallysolubilizing the AIs in a suitable matrix comprising a polymericsolubilizing agent and water in an alkylene glycol and poly(alkyleneglycol) vehicle.

The solubilizing matrix can comprise two parts. Part A is a hydrophilicmixture of a pharmaceutically acceptable alkylene glycol, such aspropylene glycol and a pharmaceutically acceptable poly(alkyleneglycol), such as a polyethylene glycol (PEG). Part B is a mixture of apharmaceutically acceptable solubilizing polymer, such as apolyvinylpyrrolidone (povidone) and water. Parts A and B are combined toform the solubilizing matrix, and the active ingredients are added tothis solubilizing matrix to form the fill composition as clearsolutions. The fill composition of the invention can then beencapsulated into capsules of the invention.

In one embodiment the pharmaceutically acceptable poly(alkylene glycol)is selected from the group consisting of poly(ethylene glycol)s (PEGs);preferably the PEGs are selected from the group consisting of PEG 200,300, 400, 600, mixtures thereof, and mixtures of these with PEG 800,1000, 2000, 3000, 4000, 5000, 6000, 7000, or 8000. In one embodiment thepharmaceutically acceptable alkylene glycol is propylene glycol. In oneembodiment of the fill composition, the pharmaceutically acceptablepolymeric solubilizing agent is a polyvinylpyrrolidone (PVP). In oneembodiment the PVP is selected from the group consisting of PVP K12, PVPK17, PVP K30, PVP K60, and PVP K90; preferably the polyvinylpyrrolidoneis PVP 12, PVP 17 or PVP 30.

As used herein, the term “analgesic” designates any of a number ofwell-known drugs which are commonly used to relieve headaches and toreduce fever. Such drugs include aspirin, acetaminophen, ibuprofen, andnaproxen, among others. For the present application a preferredanalgesic is acetaminophen.

The term “clear” as used herein with regard to the inventive fillcompositions, means transparent, without any cloudiness orprecipitation.

The term “ionizing agent” herein refers to a compound that can reactwith acetaminophen in the solvent system to form acetaminophen ions.Examples of an ionizing agent include both organic and inorganic basescapable of accepting hydrogen ions or donating electron pairs. Alkali oralkaline-earth metal salts or hydroxides are commonly used ionizingagents to increase the solubility of acetaminophen.

An ionizing agent can be added to the formulation to boost thesolubility of acetaminophen in the solvent system. However, it canundesirably accelerate the degradation of acetaminophen. Thus, anacetaminophen formulation having an ionizing agent might be less stable.Based on the required shelf life of a formulation, a person skilled inthe art can easily decide whether or not to include an ionizing agent inthe formulation. In the formulation of this invention that does notinclude an ionizing agent, acetaminophen is dissolved at an unexpectedlyhigh concentration in the solvent system, which, as pointed out above,contains polyvinylpyrrolidone, polyethylene glycol, and water.

The term “dissolving” herein means “evenly dispersing an activeingredient (e.g., acetaminophen, guaifenesin, phenylephrine,dextromethorphan, diphenhydramine, and pseudoephedrinea) as molecules inthe solvent system containing polyvinylpyrrolidone, polyethylene glycol,and water for at least three days, as judged by the naked eye or by amagnifying optical device based on two criteria: (i) transparence of thesolution, and (ii) no formation of solid precipitation.

The transitional phrase “consisting essentially of” or “consistsessentially of” as used herein limits the scope of a claim to thespecified materials or steps and those that do not materially affect thebasic and novel characteristics of the claimed invention.

Other Components

Other components which can be incorporated into the liquidpharmaceutical core compositions of the instant invention includecolorings, flavorings, preservatives, lubricants, flow-enhancers,filling aids, anti-oxidants, essences, and other aesthetically pleasingcomponents. For example, the compositions can further contain ananti-oxidant. In some embodiments the anti-oxidant is selected from thegroup consisting of BHA, BHT and mixtures thereof.

Process of Making

Another aspect of the invention is directed to a method of preparing aclear liquid softgel fill composition as disclosed above, e.g., thatshown in FIG. 2. In one example, the method comprises: (a) stirringpolyethylene glycol or a mixture of polyethylene glycols, and propyleneglycol with heating to 70° C.±10° C. (e.g., 70° C.±7° C.) until a clearsolution is obtained; (b) slowly adding polyvinylpyrrolidone in smallquantities with continuous mixing and heating to 70° C.±10° C. (e.g.,70° C.±7° C.), until a clear solution is obtained; (c) adding purifiedwater with continuous mixing and heating to 70° C.±10° C. (e.g., 70°C.±7° C.), until a clear solution is obtained; (d) adding a first activeingredient (e.g., guaifenesin) with continuous mixing and heating to 70°C.±10° C. (e.g., 70° C.±7° C.), until a clear solution is obtained; Insome examples, once guaifenesin is added, the heat is turned off but thesolution is still warm. (e) adding a second active ingredient (e.g.,dextromethorphan HBr) with continuous mixing and optionally heating to,e.g., 70° C.±10° C. (e.g., 70° C.±7° C.), until a clear solution isobtained; (f) successively adding a third active ingredient (e.g.,phenylephrine HCl) with continuous mixing and optionally heating up to80° C., until a clear solution is obtained; and (g) cooling to ambienttemperature and deaerating the clear liquid softgel fill solution. Insome embodiment of the method the polyethylene glycol is selected fromthe group consisting of PEG 400, PEG 600 and mixtures thereof. In someembodiments of the method the temperature of the solution during theaddition of dextromethorphan HBr is up to 55° C., and the temperature ofthe solution during the addition of phenylephrine HCl is below 35° C.

The liquid softgel fill formulation can be encapsulated in soft gelatinshells to form softgel capsules, for example by using a conventionalrotary die process. Suitable soft gelatin shells may include (i)gelatin, 20-60% by weight; (ii) glycerin, 0-30% by weight; (iii)sorbitol, 0-30% by weight; (iv) purified water, 20-50% by weight; and(v) artificial color, 0.0001-0.002% by weight. The highly concentratedsolution of active ingredients found in the liquid softgel fillformulations of the present invention allows the entire combination tobe encapsulated into a reasonably small sized (0.2-1.8 mL) clear softgelcapsule for easy swallowing. The inventive formulation also enhances thebioavailability of the active ingredients. Further, encapsulation of theingredients masks the negative taste of the active ingredients so thatcompliance issues with taking the medication are minimized.

The softgel capsules of the invention can also be prepared by othermethods well known in the art. See e.g., P. K. Wilkinson et al.,“Softgels: Manufacturing Considerations,” Drugs and the PharmaceuticalSciences, 41 (Specialized Drug Delivery Systems); P. Tyle, Ed. (MarcelDekker, Inc., New York, 1990) 409-449; F. S. Hom et al., “Capsules,Soft” Encyclopedia of Pharmaceutical Technology, vol. 2; J. Swarbrickand J. C. Boylan, eds. (Marcel Dekker, Inc., New York, 1990) pp.269-284; M. S. Patel et al., “Advances in Softgel FormulationTechnology,” Manufacturing Chemist, vol. 60, no. 7, pp. 26-28 (July1989); M. S. Patel et al., “Softgel Technology,” Manufacturing Chemist,vol. 60, no. 8, pp. 47-49 (August 1989); R. F. Emerson, “Softgel (SoftGelatin Capsule) Update,” Drug Development and Industrial Pharmacy(Interphex '86 Conference), vol. 12, no. 8 & 9, pp. 1133-1144 (1986);and W. R. Ebert, “Soft Elastic Gelatin Capsules: A Unique Dosage Form,”Pharmaceutical Technology, vol. 1, no. 5, pp. 44-50 (1977).

As disclosed herein, a number of ranges of values are provided. It isunderstood that each intervening value, to the tenth of the unit of thelower limit, unless the context clearly dictates otherwise, between theupper and lower limits of that range is also specifically disclosed.Each smaller range between any stated value or intervening value in astated range and any other stated or intervening value in that statedrange is encompassed within the invention. The upper and lower limits ofthese smaller ranges may independently be included or excluded in therange, and each range where either, neither, or both limits are includedin the smaller ranges is also encompassed within the invention, subjectto any specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention. Theterm “about” generally refers to plus or minus 10% of the indicatednumber. For example, “about 10%” may indicate a range of 9% to 11%, and“about 20” may mean from 18 to 22. Other meanings of “about” may beapparent from the context, such as rounding off, so, for example “about1” may also mean from 0.5 to 1.4.

Polyvinylpyrrolidone, also known as Polyvidone or Povidone, is awater-soluble polymer. Polyvinylpyrrolidone used in this invention hasan molecular weight in the range of 2,000 to 1,500,000, e.g., 2,000 to62,000, 2,000 to 4,000, 4,000 to 18,000, or 6,000 to 15,000.Polyvinylpyrrolidone products are commonly graded by K values. The Kvalue is an index for correlating relative viscosity with the averagedegree of polymerization. See Cellulose Chem. 1932, 13, 60. The K valueis calculated by the following formula:

K=(1.5 log η_(rel)−1)/(0.15+0.003c)+(300c log η_(rel)+(c+1.5c logη_(rel))²)^(1/2)/(0.15c+0.003c ²)

η_(rel): Relative viscosity of aqueous polyvinylpyrrolidone solution towater. c: Content of polyvinylpyrrolidone in an aqueouspolyvinylpyrrolidone solution (w/w %).

Polyvinylpyrrolidone used in the formulation has a K value of 12 to 90,e.g., 12, 15, 17, 25, or 30. Polyvinylpyrrolidone is designated asPovidone in the United States Pharmacopeial Convention (“USP”).Polyvinylpyrrolidone products are commercially available and generallyinclude K values in their trade names, e.g., Polyvinylpyrrolidone K17 orPovidone K17. There are correlations between K values and molecularweights. For example, polyvinylpyrrolidone K12 has a molecular weight of2,000 to 4,000, K15 6,000 to 15,000, K17 4,000 to 18,000, K30 40,000 to62,000, and K90 1,000,000 to 1,500,000. Polyvinylpyrrolidone productsfrom different vendors may have different average molecular weights,which typically fall into the ranges cited above.

Polyvinylpyrrolidone herein refers to a single product or a mixture ofseveral products. For example, it can be polyvinylpyrrolidone K12, K15,K17, K25, K30, K60, K90, or a mixture thereof. Polyvinylpyrrolidoneenhances the solubility of AIs in the solvent system containingpolyvinylpyrrolidone, polyethylene glycol, water, and optionallypropylene glycol or other components.

Polyethylene glycol, also known as “PEG,” has a formula ofH(OCH₂CH₂)_(n)OH, wherein n is 4 or greater. A number generally followsthe name PEG to indicate its average molecular weight. For example,PEG-400 has an average molecular weight of about 400. See CosmeticIngredient Dictionary, 3d Ed. (1982), pages 201-03; Merck Index, 10thEd. (1983), page 1092.

Polyethylene glycol used in this invention is a clear viscous liquid ora white solid at room temperature, and can be dissolved in water andmany organic solvents. Its molecular weight can be between 200 and 800,preferably 400-600. The solvent system can contain a single polyethyleneglycol product or a mixture of two or more polyethylene glycol products.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases including inorganicbases and organic bases. Salts derived from nonorganic bases includesodium, potassium, lithium, ammonia, calcium, magnesium, ferrous, zinc,manganous, aluminum, ferric, manganic salts and the like. Salts derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary, tertiary and quaternary amines, substitutedamines including naturally occurring substituted amines, cyclic aminesand basic ion exchange resins, such as triethylamine, tripropylamine,2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine,histidine, caffeine, procaine, N-ethylpiperidine, hydrabamine, oholine,betaine, ethylenediamine, glucosamine, methylglycamine, theobromine,purines, piperazine, piperidine, polyamine resins and the like.

EXAMPLES Example 1 Bioavailable Liquid Softgel Fill CompositionComprising Guaifenesin and Phenylephrine

A soft gelatin capsule containing a concentrated bioavailable liquidfill composition was prepared from the following ingredients.

Formulation #1 Fill Ingredients mg/capsule Weight % Polyethylene glycol400, USP 404.87 47.08% Propylene Glycol, USP 20 2.33% Povidone (K-12)USP 150 17.44% Povidone (K-30) USP 0 0.00% Purified Water, USP 80 9.30%Acetaminophen, USP 0 0.00% Guaifenesin 200 23.26% Phenylephrine HCl, USP5.13 0.60% Dextromethorphan HBR (95%) 0 0.00% Diphenhydramine HCl 00.00% Pseudoephedrine 0 0.00% Total 860 100.00%

The above ingredients were combined in the manner shown in FIG. 2 exceptno dextromethorphan HBR was added.

Soft gelatin capsules were prepared from the following gel ingredientsin a manner similar to that shown in FIG. 1 except no D&C Yellow #10,FD&C Red #40, FD&C Yellow #6, D&C Red #33 or FD&C Blue #1 was added. Theabove formulation was then encapsulated in the soft gelatin capsule andfurther processed in the manner shown in FIG. 3. The resulting softgelatin capsules are suitable for oral administration.

Gel ingredients Gelatin 150 Bloom NF Yes Glycerin USP Yes SorbitolSorbitan Solution Yes D&C Yellow#10 — FD&C Red#40 — FD&C Yellow#6 — D&CRed#33 — FD&C Blue #1 — Encapsulation lubricant Yes, trace IsopropylAlcohol, USP Yes, trace White Ink Yes, trace

Example 2 Bioavailable Liquid Softgel Fill Composition ComprisingGuaifenesin and Dextromethorphan

A soft gelatin capsule containing a concentrated bioavailable liquidfill composition was prepared from the following ingredients.

Formulation #3 Fill Ingredients mg/cap Weight % Polyethylene glycol 400,USP 404.474 46.76% Propylene Glycol, USP 20 2.31% Povidone (K-12) USP150 17.34% Povidone (K-30) USP 0 0.00% Purified Water, USP 80 9.25%Acetaminophen, USP 0 0.00% Guaifenesin 200 23.12% Phenylephrine HCl, USP0 0.00% Dextromethorphan HBR (95%) 10.526 1.22% Diphenhydramine HCl 00.00% Pseudoephedrine 0 0.00% Total 865 100.00%

The above ingredients were combined in the manner shown in FIG. 2 exceptno Phenylephrine HCl was added.

Soft gelatin capsules were prepared from the following gel ingredientsin a manner similar to that shown in FIG. 1 except only Yellow #6 wasadded. The above formulation was then encapsulated in the soft gelatincapsule and further processed in the manner shown in FIG. 3. Theresulting soft gelatin capsules are suitable for oral administration.

Gel ingredients Gelatin 150 Bloom NF Yes Glycerin USP Yes SorbitolSorbitan Solution Yes D&C Yellow#10 — FD&C Red#40 — FD&C Yellow#6 YesD&C Red#33 — FD&C Blue #1 — Encapsulation lubricant Yes, trace IsopropylAlcohol, USP Yes, trace White Ink Yes, trace

Example 3 Bioavailable Liquid Softgel Fill Composition ComprisingGuaifenesin, Phenylephrine, and Dextromethorphan

A soft gelatin capsule containing a concentrated bioavailable liquidfill composition was prepared from the following ingredients.

Formulation #4 Fill Ingredients mg/cap Weight % Polyethylene glycol 400,USP 419.224 47.37% Propylene Glycol, USP 20 2.26% Povidone (K-12) USP150 16.95% Povidone (K-30) USP 0 0.00% Purified Water, USP 80 9.04%Acetaminophen, USP 0 0.00% Guaifenesin 200 22.60% Phenylephrine HCl, USP5.25 0.59% Dextromethorphan HBR (95%) 10.526 1.19% Diphenhydramine HCl 00.00% Pseudoephedrine 0 Total 885 100.00%

The above ingredients were combined in the manner shown in FIG. 2.

Soft gelatin capsules were prepared from the following gel ingredientsin a manner similar to that shown in FIG. 1. The above formulation wasthen encapsulated in the soft gelatin capsule and further processed inthe manner shown in FIG. 3. The resulting soft gelatin capsules aresuitable for oral administration.

Gel ingredients Gelatin 150 Bloom NF Yes Glycerin USP Yes SorbitolSorbitan Solution Yes D&C Yellow#10 — FD&C Red#40 Yes FD&C Yellow#6 YesD&C Red#33 — FD&C Blue #1 — Encapsulation lubricant Yes, trace IsopropylAlcohol, USP Yes, trace White Ink Yes, trace

Example 4 Bioavailable Liquid Softgel Fill Composition ComprisingAcetaminophen, Guaifenesin, and Phenylephrine

A soft gelatin capsule containing a concentrated bioavailable liquidfill composition was prepared from the following ingredients.

Formulation #5 Fill Ingredients mg/cap Weight % Polyethylene glycol 400,USP 671.75 47.47% Propylene Glycol, USP 28 1.98% Povidone (K-12) USP 1007.07% Povidone (K-30) USP 0 0.00% Purified Water, USP 85 6.01%Acetaminophen, USP 325 22.97% Guaifenesin 200 14.13% Phenylephrine HCl,USP 5.25 0.37% Dextromethorphan HBR (95%) 0 0.00% Diphenhydramine HCl 00.00% Pseudoephedrine 0 0.00% Total 1415 100.00%

The above ingredients were combined in the manner shown in FIG. 2 exceptthat acetaminophen was added and no dextromethorphan HBR was added.

Soft gelatin capsules were prepared from the following gel ingredientsin a manner similar to that shown in FIG. 1 except that no FD&C Red #40,FD&C Yellow #6, D&C Red #33 or FD&C Blue #1 was added while D&C Yellow#10 is added. The above formulation was then encapsulated in the softgelatin capsule and further processed in the manner shown in FIG. 3. Theresulting soft gelatin capsules are suitable for oral administration.

Gel ingredients Gelatin 150 Bloom NF Yes Glycerin USP Yes SorbitolSorbitan Solution Yes D&C Yellow#10 Yes FD&C Red#40 — FD&C Yellow#6 —D&C Red#33 — FD&C Blue #1 — Encapsulation lubricant Yes, trace IsopropylAlcohol, USP Yes, trace White Ink Yes, trace

Example 5 Bioavailable Liquid Softgel Fill Composition ComprisingAcetaminophen, Phenylephrine, and Diphenhydramine

A soft gelatin capsule containing a concentrated bioavailable liquidfill composition was prepared from the following ingredients.

Formulation #6 Fill Ingredients mg/cap Weight % Polyethylene glycol 400,USP 684.75 55.22% Propylene Glycol, USP 50 4.03% Povidone (K-12) USP 00.00% Povidone (K-30) USP 65 5.24% Purified Water, USP 85 6.85%Acetaminophen, USP 325 26.21% Guaifenesin 0 0.00% Phenylephrine HCl, USP5.25 0.42% Dextromethorphan HBR (95%) 0 0.00% Diphenhydramine HCl 252.02% Pseudoephedrine 0 Total 1240 100.00%

The above ingredients were combined in the manner shown in FIG. 2 exceptthat (i) acetaminophen and diphenhydramine HCl were added and (ii)neither guaifenesin nor dextromethorphan HBR was added.

Soft gelatin capsules were prepared from the following gel ingredientsin a manner similar to that shown in FIG. 1 except that no D&C Yellow#10, FD&C Red #40, or FD&C Yellow #6 was added while D&C Red #33 andFD&C Blue #1 were added. The above formulation was then encapsulated inthe soft gelatin capsule and further processed in the manner shown inFIG. 3. The resulting soft gelatin capsules are suitable for oraladministration.

Gel ingredients Gelatin 150 Bloom NF Yes Glycerin USP Yes SorbitolSorbitan Solution Yes D&C Yellow#10 — FD&C Red#40 — FD&C Yellow#6 — D&CRed#33 Yes FD&C Blue #1 Yes Encapsulation lubricant Yes, trace IsopropylAlcohol, USP Yes, trace White Ink Yes, trace

Example 6 Bioavailable Liquid Softgel Fill Composition ComprisingGuaifenesin and Pseudoephedrine

A soft gelatin capsule containing a concentrated bioavailable liquidfill composition is prepared from the following ingredients: Guaifenesin(200 mg) and Pseudoephedrine (30 mg) per 850-890 mg per capsule. Theabove ingredients are combined in a manner similar to that shown in FIG.2. Soft gelatin capsules are prepared in a manner similar to that shownin FIG. 1. The above formulation is then encapsulated in the softgelatin capsule and further processed in the manner shown in FIG. 3. Theresulting soft gelatin capsules are suitable for oral administration.

The foregoing examples and description of the preferred embodimentsshould be taken as illustrating, rather than as limiting the presentinvention as defined by the claims. As will be readily appreciated,numerous variations and combinations of the features set forth above canbe utilized without departing from the present invention as set forth inthe claims. Such variations are not regarded as a departure from thescope of the invention, and all such variations are intended to beincluded within the scope of the following claims. All references citedherein are incorporated by reference in their entireties.

1. A clear bioavailable liquid composition comprising: (a) two or moreactive ingredients selected from the group consisting of: acetaminophen,guaifenesin, phenylephrine and/or a pharmaceutically acceptable saltthereof, dextromethorphan and/or a pharmaceutically acceptable saltthereof, diphenhydramine and/or a pharmaceutically acceptable saltthereof, and pseudoephedrine and/or a pharmaceutically acceptable saltthereof; (b) a matrix comprising:
 1. 20-70 wt % of a pharmaceuticallyacceptable poly(alkylene glycol), and
 2. 0.5-8 wt % of apharmaceutically acceptable alkylene glycol; and (c) a solubilizingagent comprising: 1-30 wt % of a pharmaceutically acceptable polymericsolubilizing agent, and 1-10 wt % by weight water; wherein said wt %values are based on the total weight of the composition, and whereinsaid fill composition is clear.
 2. The clear bioavailable liquidcomposition of claim 1, wherein the matrix comprises: 40-60 wt % of apharmaceutically acceptable poly(alkylene glycol), and 1-6 wt % of apharmaceutically acceptable alkylene glycol.
 3. (canceled)
 4. The clearbioavailable liquid composition of claim 1, wherein the solubilizingagent comprises: 4-20 wt % of a pharmaceutically acceptable polymericsolubilizing agent, and 5-10 wt % by weight water.
 5. (canceled)
 6. Theclear bioavailable liquid composition of claim 1, comprising: 0 to about30.0 wt % acetaminophen, 0 to about 25.0 wt % guaifenesin, 0 to about1.0 wt % phenylephrine HCl. 0 to about 2.0 wt % dextromethorphan HBr, 0to about 3.0 wt % diphenhydramine HCl, or 0 to about 5.0 wt %pseudoephedrine HCl; provided that at least two active ingredients arepresent in >0 wt %.
 7. The clear bioavailable liquid composition ofclaim 1, comprising the following as the only active ingredients: about22.0 to about 25.0 wt % guaifenesin and about 0.5 to 0.7 wt %phenylephrine HCl.
 8. The clear bioavailable liquid composition of claim7, wherein the composition is about 860 mg comprising: about 200 mgguaifenesin, about 5.13 mg phenylephrine HCl, about 404.87 mgpolyethylene glycol 400, about 20 mg propylene glycol, about 150 mgPovidone (k12), and about 80 mg water.
 9. (canceled)
 10. The clearbioavailable liquid composition of claim 1, comprising the following asthe only active ingredients: about 22.0 to about 25.0 wt % guaifenesinand about 1.0 to 2.0 wt % dextromethorphan HBr (95%).
 11. The clearbioavailable liquid composition of claim 10, wherein the composition isabout 865 mg comprising: about 200 mg guaifenesin, about 10.526 mgdextromethorphan HBR (95%), about 404.474 mg polyethylene glycol 400,about 20 mg propylene glycol, about 150 mg Povidone (k12), and about 80mg water.
 12. (canceled)
 13. The clear bioavailable liquid compositionof claim 1, comprising the following as the only active ingredients:about 21.0 to about 24.0 wt % guaifenesin, about 0.40 to about 1.0 wt %phenylephrine HCl, and about 1.0 to 2.0 wt % dextromethorphan HBr (95%).14. The clear bioavailable liquid composition of claim 13, wherein thecomposition is about 885 mg comprising: about 200 mg guaifenesin, about5.25 mg phenylephrine HCl, about 10.526 mg dextromethorphan HBr (95%),about 419.224 mg polyethylene glycol 400, about 20 mg propylene glycol,about 150 mg Povidone (k12), and about 80 mg water.
 15. (canceled) 16.The clear bioavailable liquid composition of claim 1, comprising thefollowing as the only active ingredients: about 21.0 to about 24.0 wt %acetaminophen, about 13.0 to about 16.0 wt % guaifenesin, and about 0.2to about 0.6 wt % phenylephrine HCl.
 17. The clear bioavailable liquidcomposition of claim 16, wherein the composition is about 1415 mgcomprising: about 325 mg acetaminophen, about 200 mg guaifenesin, about5.25 mg phenylephrine HCl, about 671.75 mg polyethylene glycol 400,about 28 mg propylene glycol, about 100 mg Povidone (k12), and about 85mg water.
 18. (canceled)
 19. The clear bioavailable liquid compositionof claim 1, comprising the following as the only active ingredients:about 25.0 to about 28.0 wt % acetaminophen, about 0.30 to about 0.60 wt% phenylephrine HCl, and about 1.0 to about 3.0 wt % diphenhydramineHCl.
 20. The clear bioavailable liquid composition of claim 19, whereinthe composition is about 1240 mg comprising: about 325 mg acetaminophen,about 5.25 mg phenylephrine HCl, about 25 mg diphenhydramine HCl, about684.75 mg polyethylene glycol 400, about 50 mg propylene glycol, about65 mg Povidone (k30), and about 85 mg water.
 21. (canceled)
 22. Theclear bioavailable liquid composition of claim 1, comprising thefollowing as the only active ingredients: about 21.0 to about 25.0 wt %guaifenesin and about 2 to 5 wt % pseudoephedrine HCl.
 23. The clearbioavailable liquid composition of claim 22, wherein the composition isabout 850-890 mg comprising: about 200 mg guaifenesin and about 30 mgpseudoephedrine HCl.
 24. The clear bioavailable liquid composition ofclaim 1, comprising only two or three active ingredients selected fromthe group (a).
 25. The clear bioavailable liquid composition of claim24, wherein said two or three active ingredients are the only activeingredients.
 26. A pharmaceutical composition in the form of a softgelatin capsule of a size suitable for easy swallowing and typicallycontaining from about 100 mg to about 2000 mg of a solubilizedpharmaceutical active composition, comprising: (a) an outer gelatinshell; and (b) a safe and effective mount of the clear bioavailableliquid composition of claim 1 which is encapsulated by said outergelatin shell.
 27. A pharmaceutical composition in the form of a softgelatin capsule of a size suitable for easy swallowing and typicallycontaining from about 100 mg to about 2000 mg of a solubilizedpharmaceutical active composition, comprising: (a) an outer gelatinshell; and (b) a safe and effective mount of the clear bioavailableliquid composition of claim 6 which is encapsulated by said outergelatin shell.